Methods And Systems For Delivering Substances Into Luminal Walls

ABSTRACT

Angioplasty and other dilatation devices are provided with scoring elements which incorporate a drug to be delivered to a body lumen, typically a blood vessel. The scoring elements have drugs and other active substances coated over a portion thereof or incorporated within internal structure of the element so that the drug is released into the luminal wall closely associated diseased regions of the body lumen as the scoring structure is radially expanded into the wall.

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application is a divisional of co-pending U.S. patentapplication Ser. No. 11/411,635, filed on Apr. 26, 2006, which claimsbenefit to U.S. Patent Application Ser. No. 60/680,450, filed May 11,2005, the full disclosure of which is incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention. The present invention relates to the field ofmedical devices, more specifically to medical devices intended to treatstenoses in the vascular system.

Balloon dilatation (angioplasty) is a common medical procedure mainlydirected at revascularization of stenotic vessels by inserting acatheter having a dilatation balloon through the vascular system. Theballoon is inflated inside a stenosed region in a blood vessel in orderto apply radial pressure to the inner wall of the vessel and widen thestenosed region to enable better blood flow.

In many cases, the balloon dilatation procedure is immediately followedby a stenting procedure where a stent is placed to maintain vesselpatency following the angioplasty. Failure of the angioplasty balloon toproperly widen the stenotic vessel, however, may result in improperpositioning of the stent in the blood vessel. If a drug-eluting stent isused, its effectiveness may be impaired by such improper positioning andthe resulting restenosis rate may be higher. This is a result of severalfactors, including the presence of gaps between the stent and the vesselwall, calcified areas that were not treated properly by the balloon, andothers.

Conventional balloon angioplasty suffers from a number of othershortcomings as well. In some cases the balloon dilatation procedurecauses damage to the blood vessel due to aggressive balloon inflationthat may stretch the diseased vessel beyond its elastic limits. Suchover inflation may damage the vessel wall and lead to restenosis of thesection that was stretched by the balloon. In other cases, slippage ofthe balloon during the dilatation procedure may occur. This may resultin injury to the vessel wall surrounding the treated lesion. Oneprocedure in which slippage is likely to happen is during treatment ofin-stent restenosis, which at present is difficult to treat byangioplasty balloons. Fibrotic lesions are also hard to treat withconventional balloons, and elastic recoil is usually observed aftertreatment of these lesions. Many long lesions have fibrotic sectionsthat are difficult to treat using angioplasty balloons.

To overcome at least some of these problems, U.S. Pat. No. 5,320,634describes the addition of cutting blades to the balloon. The blades cancut the lesions as the balloon is inflated. U.S. Pat. No. 5,616,149describes a similar method of attaching sharp cutting edges to theballoon. U.S. Patent Publication 2003/0032973 describes a stent-likestructure having non-axial grips for securing an angioplasty balloonduring inflation. U.S. Pat. No. 6,129,706 describes a balloon catheterhaving bumps on its outer surface. U.S. Pat. No. 6,394,995 describes amethod of reducing the balloon profile to allow crossing of tightlesions. U.S. Patent Publication 2003/0153870 describes a balloonangioplasty catheter having flexible elongate elements that createlongitudinal channels in a lesion or stenosis.

While the use of angioplasty balloons having cutting blades has provedto be a significant advantage under many circumstances, the presentcutting balloon designs and methods for their use continue to sufferfrom shortcomings. Most commercial cutting balloon designs, includingthose available from INTERVENTIONAL TECHNOLOGIES, INC., of San Diego,Calif., now owned by BOSTON SCIENTIFIC, of Natick, Mass., haverelatively long, axially aligned blades carried on the outer surface ofan angioplasty balloon. Typically, the blades are carried on arelatively rigid base directly attached to the outer balloon surface.The addition of such rigid, elongated blade structures makes the balloonitself quite stiff and limits the ability to introduce the balloonthrough torturous regions of the vasculature, particularly the smallervessels within the coronary vasculature. Moreover, the cutting balloonscan be difficult to deflate and collapse, making removal of the balloonsfrom the vasculature more difficult than with corresponding angioplastyballoons which do not include cutting blades. Additionally, the axiallyoriented cuts imparted by such conventional cutting balloons do notalways provide the improved dilatation and treatment of fibrotic lesionswhich would be desired.

In addition to the above, drug eluting stents (DES), although verysuccessful, are not suitable for every patient. Patients undergoing DESimplantation are kept under a regimen of anti-coagulant therapy for anextended period of time to minimize risk of late thrombosis.Anticoagulants may cause excessive bleeding and are not recommended forpeople who are suffering from certain other health problems and/or whomight need surgery. Some patients are intolerant to anticoagulants.

For all of these reasons, it would be desirable to provide improvedmethods, catheters, and systems for performing angioplasty and othervascular interventions for treating vascular occlusive diseases,including but not limited to treatment of hardened and calcified plaque.It would be particularly desirable if such methods and systems could beutilized for other body lumens beyond the vasculature. In particular, itwould be desirable to provide methods and systems which could utilizeboth conventional and novel balloon scoring and cutting structures fordelivering therapeutic agents to blood vessels and other body lumens.Such methods and systems could thus disrupt vascular and luminalocclusions in a manner provided by conventional scoring and cuttingstructures while simultaneously delivering therapeutic agents to theblood vessel, and more particularly to the intimal and subintimalregions of the blood vessel which can be accessed by the cutting elementin order to enhance distribution of the therapeutic agents. At leastsome of these objectives will be met by the inventions described hereinbelow.

2. Description of the Background Art. The following U.S. patents andprinted publication relate to cutting balloons and balloon structures:6,450,988; 6,425,882; 6,394,995; 6,355,013; 6,245,040; 6,210,392;6,190,356; 6,129,706; 6,123,718; 5,891,090; 5,797,935; 5,779,698;5,735,816; 5,624,433; 5,616,149; 5,545,132; 5,470,314; 5,320,634;5,221,261; 5,196,024; and Published U.S. Patent Application2003/0032973. Other U.S. patents of interest include 6,454,775;5,100,423; 4,998,539; 4,969,458; and 4,921,984. The following patentsdescribe drug delivery catheters having needle based deliverymechanisms: U.S. Pat. No. 4,578,061, describes needle injectioncatheters having deflectable, axially advanceable needles. U.S. Pat. No.5,538,504, describes a needle injection catheter having a transverselyoriented needle that is laterally advanced by a balloon driver. Also ofinterest are U.S. Pat. Nos. 6,319,230; 6,283,951; 6,283,947; 6,004,295;5,419,777; and 5,354,279. Drug coated stents and angioplasty balloonsare described in numerous patents and published applications includingU.S. Pat. Nos. 6,280,411; 6,656,156; 6,682,545; and Publication Nos.U.S.2004/0193257; U.S.2004/0208985; and U.S.2005/0033417.

BRIEF SUMMARY OF THE INVENTION

The present invention provides methods and apparatus for deliveringactive substances to luminal sites, and in particular for deliveringanti-hyperplasia substances to diseased sites in a patient's vascularsystem, such as sites of thrombosis and plaque in a patient's arteries.Methods for delivering active substance to a luminal site comprisepositioning a scoring element within the body lumen and advancing thescoring element to score a wall of the body lumen. The scoring elementcomprises the active substance to be delivered to the luminal site. Byinitially scoring an exposed surface of the luminal wall or a lesion,the active substance can be released to locations in or beneath theintimal layer of the vessel wall, typically to a depth in the range from0.001 mm to 1 mm, usually from 0.01 mm to 0.1 mm. In the case oftreatment of arterial sites, the scoring can not only deliver the drugto regions within the thrombus or plaque, it can further score thevascular wall and deliver the drug into the intimal and subintimallayers surrounding the blood vessel.

In addition to treatment of blood vessels, the methods and systems ofthe present invention can be used to treat a variety of other bodylumens, including vein grafts and synthetic grafts, as well as lumens ofthe respiratory, urinary, reproductive and digestive systems, and thelike.

The benefits of drug delivery using a scoring or cutting device includerapid (short term) release to intimal and subintimal areas rather thansustained delivery over few days or weeks with DES (constantconcentration over time). The combination of scoring the lesion to opendiffusion channels and delivering therapeutic agent directly to thediffusion channels increases the efficacy of the system.

The methods and systems of the present invention are particularly usefulfor delivering drugs which are hydrophobic and lipophilic. Thehydrophobic nature of some drugs (e.g. paclitaxel and sirulimus) and thefact that those drugs are lipophilic (i.e. high affinity to liposome)help retain the drug for longer time in the lesion and minimize the lossof drug during the time of delivery due to dissolution in the blood.

Given the above, the characteristics of the polymer matrix may be verydifferent from stents. Ideally the drug diffuses over a short period oftime (few seconds to several minutes in the case of the circulationsystem) to the lesion not to diffuse over time (days or weeks). Manydifferent polymers can be used including polymers that will dissolve inblood within the interaction time and those that will not dissolve butwill release drug.

The scoring element(s) are typically positioned using an intravascularor other intraluminal catheter which carries one or more scoringelements at or near its distal end. In the case of blood vessels, thecatheter is typically introduced over a guidewire in a conventionalmanner, e.g., through the femoral artery to reach the coronary arteriesor through a sheath in case of peripheral arteries.

The scoring element(s) may be advanced to score a plaque in a body lumenby radially advancing the scoring elements into the lesion and theluminal wall. Typically, such radial expansion is achieved using anexpandable shell, such as an inflatable balloon carried by the catheter.Alternatively, the radial expansion can be achieved using self-expandingmaterials such as nitinol or expandable geometries using other materials(such as stainless steel). Scoring elements may have any of thegeometries previously used in scoring devices, including the lineargeometries of the scoring elements employed in the IVT devices, asdescribed above. Preferably, however, the scoring elements will compriseone or more resilient elements having helical geometries, as taught byco-pending patent application Ser. Nos. 10/631,499, filed on Jul. 30,2003; 10/810,330, filed on Mar. 25, 2004; and 10/917,917, filed on Aug.13, 2004, assigned to the assignee of the present application, the fulldisclosures of which are incorporated herein by reference.

Regardless of the geometry of the scoring elements, radial advancementwill usually comprise expanding an expandable shell, such as aninflatable balloon, which carries at least one scoring element. In thisway, the outward edge(s) of the scoring element can engage and penetratethe luminal wall and/or the occlusive or other material which covers atleast a portion of the luminal wall. Alternatively, the radial expansioncan be achieved using self-expanding materials such as nickel titaniumalloys or expandable geometries using other materials (such as stainlesssteel). The scoring element can be expanded by other means by usingtemperature controlled structures (i.e. made of heat memory alloys) ormechanical means such as internal sliders with an increased diameter.

The methods, catheters, and systems of the present invention can beutilized to deliver a wide variety of active substances, including drugsuseful for treating a wide variety of luminal diseases and conditions.The methods and apparatus of the present invention are particularlyuseful for delivering a wide variety of therapeutic and pharmaceuticalagents, referred to collectively herein as active substances,particularly those suitable for treating vascular and other luminalconditions, including:

(1) antiproliferative and antimitotic agents such as natural productssuch as vinca alkaloids (i.e. vinblastine, vincristine, andvinorelbine), paclitaxel, epidipodophyllotoxins (i.e. etoposide,teniposide), antibiotics (dactinomycin, actinomycin D, daunorubicin,doxorubicin and idarubicin), anthracyclines, mitoxantrone, bleomycins,plicamycin (mithramycin) and mitomycin, enzymes (L-asparaginase whichsystemically metabolizes L-asparagine and deprives cells which do nothave the capacity to synthesize their own asparagine);

(2) antiplatelet agents such as G(GP) II.b/III.a inhibitors andvitronectin receptor antagonists;

(3) alkylating agents such as nitrogen mustards (mechlorethamine,cyclophosphamide and analogs, melphalan, chlorambucil), ethyleniminesand methylmelamines (hexamethylmelamine and thiotepa), alkylsulfonates-busulfan, nirtosoureas (carmustine (BCNU) and analogs,streptozocin), trazenes-dacarbazinine (DTIC);

(4) antiproliferative and antimitotic antimetabolites such as folic acidanalogs (methotrexate), pyrimidine analogs (fluorouracil, floxuridine,and cytarabine), purine analogs and related inhibitors (mercaptopurine,thioguanine, pentostatin and 2-chlorodeoxyadenosine {cladribine});

(5) platinum coordination complexes such as cisplatin, carboplatin,procarbazine, hydroxyurea, mitotane, and aminoglutethimide;

(6) hormones (e.g. estrogen);

(7) anticoagulants (heparin, synthetic heparin salts and otherinhibitors of thrombin);

(8) fibrinolytic agents (such as tissue plasminogen activator,streptokinase and urokinase), aspirin, dipyridamole, ticlopidine,clopidogrel, abciximab;

(9) antimigratory agents;

(10) antisecretory agents (breveldin);

(11) anti-inflammatory agents, such as adrenocortical steroids(cortisol, cortisone, fludrocortisone, prednisone, prednisolone,6.alpha.-methylprednisolone, triamcinolone, betamethasone, anddexamethasone), non-steroidal agents (salicylic acid derivatives i.e.aspirin); para-aminophenol derivatives i.e. acetaminophen;

(12) indole and indene acetic acids (indomethacin, sulindac, andetodalac), heteroaryl acetic acids (tolmetin, diclofenac, andketorolac), arylpropionic acids (ibuprofen and derivatives), anthranilicacids (mefenamic acid, and meclofenamic acid), enolic acids (piroxicam,tenoxicam, phenylbutazone, and oxyphenthatrazone), nabumetone, goldcompounds (auranofin, aurothioglucose, gold sodium thiomalate);

(13) immunosuppressive agents such as cyclosporine, tacrolimus (FK-506),sirolimus (rapamycin), azathioprine, mycophenolate, mofetil;

(14) angiogenic agents such as vascular endothelial growth factor(VEGF), fibroblast growth factor (FGF);

(15) angiotensin receptor blockers;

(16) nitric oxide donors;

(17) anti-sense oligionucleotides and combinations thereof;

(18) cell cycle inhibitors, mTOR inhibitors, and growth factor receptorsignal transduction kinase inhibitors;

(19) retenoids;

(20) cyclin/CDK inhibitors;

(21) HMG co-enzyme reductase inhibitors (statins); and

(22) protease inhibitors.

The present invention further comprises catheters for delivering activesubstances to body lumens. Catheters of the present invention comprise acatheter body having a proximal end and a distal end and a scoringelement disposed near the distal end. The scoring element comprises anactive substance that is delivered to a luminal wall scored or cut bythe scoring element. The active substance may be provided on or withinthe scoring element in a variety of ways. For example, the activesubstance may be coated over at least a portion of an exposed surface ofthe scoring element, typically by dipping, spraying, painting, plasmadeposition, electroplating, centrifuge systems or the like. Moretypically, however, the active substance may be incorporated in apolymeric carrier. Suitable polymeric carriers may be resorbable, suchas those comprising polylactic acids (PLA), polyglycolic acids (PLG),collagens, and the like. Alternatively, the polymeric carrier may be aporous but non-resorbable material such as porous silicon orpolyethylene. Hydrogels such as Poly Ethylene Oxide (PEO) may be usedand release the drug through swelling and erosion. Degradable polymerswhich include polyhydroxyalkanoate can be used as well. The polymer cancoat the scoring element struts or alternatively can create a filmbetween at least some of the scoring element struts or any combinationof the above.

Coatings may comprise a polymer matrix such as vinylpyrrolidone-vinylacetate, styrene acrylic polymer, ethylene acrylic acid copolymer,carboxyl function acrylic polymer, hydroxyl function acrylic polymer,and acrylic dispersion polymer, among others. In some cases it isdesirable to use a coherent bond coat (i.e. epoxies, acetals, acrylics,ethylene copolymers, or other suitable groups). Coatings may alsocomprise poly(glycol methacrylate), poly(methyl methacrylate),poly(ethyl methacrylate), poly(butyl methacrylate), poly(sulfanato ethylmethacrylate), poly(ethylene-co-vinyl acetate), poly(ethyl acrylate),poly(urethane-acrylate), poly(acrylamide-co-ethyl methacrylate),poly(divinyl benzene), poly(triethylene glycol-co-divinyl ether),poly(tri-methylol propane triacrylate), poly(pentaerythritoltetraacrylate), poly(bisphenol A ethoxylate diacrylate), poly(allylether), poly(diallyl maleate), poly(vinylidene fluoride), poly(triallylisocyanurate), poly vinyl alcohol, ethylene vinyl alcohol copolymer, oralike. The drug may also be carried on the surface of the scoringelement using an oxide layer or porous oxide layer. Alternatively thescoring element may be coated by drug without any polymer or carryingmatrix of any kind.

As an alternative to coating, the active substances, either with orwithout a polymer carrier, may be incorporated into apertures, such asholes, grooves, or wells formed in the scoring element. The aperturesmay be distributed over the entire surface of the scoring element, ormay be provided over only portions thereof. The active substances willthus be released from the apertures when the scoring elements areengaged against the luminal wall.

Scoring elements may have any conventional geometry, generally asdescribed above, including linear, helical, or other geometries. In theexemplary embodiments, the scoring elements will be formed as at least aportion of a resilient cage which surrounds an expandable shell carriedby the treatment catheter. The resilient cage will have a structurewhich expands with shell expansion and collapses over the shell, e.g.,helping to deflate a balloon which carries the cage.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1, 1A, 1B, and 1C are schematic illustrations of the balloonscoring structure embodiment in accordance with an embodiment of theinvention.

FIG. 2 is a schematic illustration of an exemplary helical scoringstructure embodiment in accordance with embodiments of the invention.

FIG. 3 is a schematic illustration of an expanded angioplasty ballooncarrying a helical scoring structure in accordance with embodiments ofthe invention.

FIG. 4 illustrates a scoring structure comprising an alternatingserpentine pattern of intermediate scoring elements between a pair ofend collars.

FIG. 5 illustrates the serpentine scoring elements of the embodiment ofFIG. 4 shown in a rolled-out configuration.

FIG. 6 illustrates a scoring structure comprising alternating C-shapedscoring elements between a pair of end collars.

FIG. 7 illustrates the C-shaped scoring elements of the embodiment ofFIG. 6 shown in a rolled-out configuration.

FIG. 8 is a view of one of the C-shaped scoring elements taken alongline 8-8 of FIG. 6.

FIG. 9 illustrates an alternative double C-shaped scoring element whichcould be utilized on a scoring structure similar to that illustrated inFIG. 6.

FIG. 10 illustrates an alternative embodiment of a helical scoringstructure comprising serpentine and zigzag structures for mounting ontoa balloon catheter.

FIG. 11 illustrates a first of the serpentine mounting elements of thescoring structure of FIG. 10.

FIG. 12 illustrates a second of the serpentine mounting elements of thescoring structure of FIG. 10.

FIG. 13 illustrates an alternative mounting structure for a helical orother scoring structure.

FIG. 14 illustrates the mounting structure of FIG. 13 shown in arolled-out configuration.

FIG. 15 shows yet another embodiment of a mounting element for thescoring structures of the present invention.

FIG. 16 illustrates the mounting structure of FIG. 15 shown in arolled-out configuration.

FIG. 17 a illustrates yet another alternative embodiment of a catheterconstructed in accordance with the principles of the present invention,where an attachment structure is disposed between the scoring structureand the catheter body.

FIG. 17 b illustrates the structure of FIG. 17 a shown without theballoon.

FIGS. 18 a-c illustrate a catheter constructed in accordance with theprinciples of the present invention having an attachment structure withvarious patterned perforations.

FIG. 19 illustrates another embodiment of a catheter constructed inaccordance with the principles of the present invention having a taperedattachment structure.

FIG. 20 illustrates yet another alternative embodiment of a catheterconstructed in accordance with the principles of the present invention,where an attachment structure is connected to a manipulator.

FIG. 21 illustrates an embodiment of the invention having a laminatedsection at the distal end of the compliance tube.

FIG. 22 illustrates another view of the embodiment of FIG. 21.

FIG. 23 illustrates the embodiment of FIG. 21 with an expandable ballooninserted within the scoring structure.

FIG. 24 illustrates an embodiment with a sleeve over the distal end ofthe scoring structure.

FIG. 25 illustrates a method of the present invention utilizing aninsertion tube to mount the scoring structure over the expandableballoon.

FIG. 26 illustrates shows the insertion tube inserted over theexpandable balloon.

FIG. 27 illustrates a scoring catheter of the present invention with theinsertion tube removed.

FIGS. 28-34 illustrate different configurations for coating or otherwisecoupling an active substance on or within a scoring element inaccordance with the principles of the present invention.

FIGS. 35, 36A, and 36B illustrate use of the scoring elements of thepresent invention for delivering an active substance to a wall site in ablood vessel.

DETAILED DESCRIPTION OF THE INVENTION

In the following description, various aspects of the present inventionwill be described. For purposes of explanation, specific configurationsand details are set forth in order to provide a thorough understandingof the present invention. However, it will also be apparent to oneskilled in the art that the present invention may be practiced withoutthe specific details presented herein. Furthermore, well-known featuresmay be omitted or simplified in order not to obscure the presentinvention.

Embodiments of the present invention relate to device forrevascularization of stenotic vessels and specifically to a ballooncatheter having external elements. The dilatation device comprises aconventional dilatation balloon such as a polymeric balloon and aspiral, or external elements with other configurations mounted on theballoon catheter. The apparatus comprise one or more scoring elementswhich are coated or otherwise loaded with an active substance to bereleased into a blood vessel wall or stenotic region in accordance withthe principles of the present invention. The invention will also finduse in treating other body lumens, such as vein and synthetic grafts, aswell as lumens of the respiratory, urinary, reproductive and digestivesystems, and the like, for other conditions such as lesions or tumors orsome types of cancer or other local disorders.

Reference is now made to FIGS. 1, 1A, and 1B, which are schematicillustrations of a dilatation device 10 in accordance with embodimentsof the invention. The devices will first be described withoutincorporation of a drug or other active substance. Particular methodsand structure for incorporating such drugs and substances are describedin detail below. The dilatation device 10 includes a dilatation balloon12, which may be any conventional angioplasty balloon such as commonlyused by interventional cardiologists or radiologists, and a helical orspiral unit 14 mounted over or attached to dilatation balloon 12. Thecompliance of the balloon and the scoring element(s) should be chosen toassure uniform expansion of the balloon substantially free from“dog-boning” as the combined structure expands within a lesion. If acompliant or a semi-compliant balloon is used and the compliance of thescoring element was not matched to comply with the properties of theballoon, the expansion of the balloon-scoring element system will not beuniform. This non-uniformity may impair the efficacy of the scoringcatheter and, in some cases, may result in poor performance. Forexample, under given pressure, certain parts of the balloon will be ableto expand while other parts will be constrained by excessive resistanceof the scoring elements.

Helical unit 14 is typically made of nitinol. Helical unit 14 may bemade of other metals such stainless steel, cobalt-chromium alloy,titanium, and the like. Alternatively, spiral unit 14 may be a polymericspiral, or made of another elastic material. Helical unit 14 may beattached at its proximal and distal ends to the proximal end 17 anddistal end 18 of dilatation balloon 12. Alternatively, spiral unit 14may be attached to the distal end and/or the proximal end of dilatationballoon 12 by collar-like attachment elements 15 and 16. Spring or othercompliant elements may be alternatively or additionally provided as partof the attachment elements to accommodate shortening of the helical unitas it is expanded.

Dilatation device 10 is inserted into the vascular system, for example,using a conventional catheter procedure, to a region of stenoticmaterial 22 of blood vessel 20. (The term “stenotic” is used herein torefer to the vascular lesion, e.g., the narrowed portion of the vesselthat the balloon is meant to open.) At the stenotic area, the dilatationballoon 12 is inflated, for example, by liquid flow into the balloon.Helical unit 14 widens on the inflated dilatation balloon 12. Oninflation, the dilatation balloon 12 together with the helical unit 14is pressed against the walls of blood vessel 20 as shown in FIG. 1B.

Reference is now made to FIG. 1C, illustrating blood vessel 20 after thedeflation of dilatation balloon 12. Helical unit 14 narrows whendeflating the dilatation balloon 12, thus the dilatation device 10 isnarrowed and may be readily retrieved from blood vessel 20. Thedeflation profile of the balloon 10 is low and mainly circular. Thestenotic material 22 in blood vessel 20 is pressed against blood vessel20 walls to widen the available lumen and enhance blood flow. Thepressing of helical unit 14 against the walls of blood vessel 20 causesscoring 23 in the stenotic area.

Reference is now made to FIG. 3 that shows a scoring structure in theform of a single wire 24 wrapped around a dilatation balloon 12 in ahelical configuration.

In other embodiments, the scoring structure of the present invention canhave a non-helical configuration. Any design of scoring structure thatcan accommodate an increase in the diameter of the balloon 12 uponinflation, and return to its configuration when the balloon is deflated,is an appropriate design useful in the invention. At least a portion ofthe scoring elements will not be parallel to the longitudinal axis ofthe balloon catheter to enhance flexibility and improve scoring.

Referring again to FIGS. 1A-1C, helical unit 14 is pushed outwardly bythe inflation of the balloon 12, and is stretched by the inflation ofthe balloon. When the balloon is deflated, helical unit 14 assists inthe deflation by its elastic recoil. This active deflation is faster andalso leads to a low profile of the deflated balloon. The balloon 12 isdisposed within the helical unit 14, which returns to its pre-inflatedshape and forces the balloon to gain a low radial profile.

In another embodiment of the invention, dilatation device 10 may carry astent. The stent can be crimped over the helical unit 14. In this way,the helical unit 14 can push the stent against hard areas of the lesion,enabling proper positioning of the stent against the vessel wall, evenin hard-calcified lesions without pre-dilation.

Reference is now made to FIG. 2, illustrating the helical unit 14 inaccordance with embodiments of the invention. Helical unit 14 istypically made of nitinol. Helical unit 14 includes three wires 19 thatare attached to collars 15 and 16 at the proximal end and distal end,respectively. Alternatively the scoring structure may be formed as ametallic cage, which can be made from a slotted tube, or polymeric cageor polymeric external elements. Alternatively the scoring structure maycomprise wires of other elements attached directly to the balloonmaterial or close to the balloon ends.

Wires 19 (FIG. 2) are attached between collars 15 and 16. The diameterof the wires is typically in the range of 0.05 mm to 0.5 mm.Alternatively, a cage (for example a metallic cage made of a slottedtube) can be used in several configurations that allow local stressconcentrations. The size and shape of the cross section of the cageelements or the cross section of the wires can vary. The cross sectioncan be a circle, rectangle, triangle, or other shape.

In alternative embodiments, the wires 19 may comprise short segmentsthat are attached to the balloon 12.

In further alternative embodiments of the invention, the helical unit 14may be glued, thermally bonded, fused, or mechanically attached at oneor both ends to dilatation balloon 12.

In yet another embodiment, a scoring structure may comprise wires thatare attached to the dilatation balloon 12 in a helical configuration orother configuration. The wires may be thermally attached to the balloon12, glued, mechanically attached, or the like.

In still another embodiment, a scoring structure comprises wire or cageelements that are not parallel to the longitudinal axis of the balloon12 so that the combination of the scoring structure 19 and the balloon12 remains flexible.

In additional embodiments, the combination of dilatation balloon 12 anda scoring structure scores the lesion and provides better vesselpreparation for drug eluting stents by allowing better positioning ofthe stent against the vessel wall and diffusion of the drug through thescores in the lesion.

In these embodiments, the balloon can be used as a platform to carrydrugs to the lesion where scoring of the lesion can enhance delivery ofthe drug to the vessel wall.

In these embodiments, the balloon can be used for a local drug deliveryby embedding drug capsules, drug containing polymer, and the like,through the stenotic material and into the vessel wall.

From the above, it can be seen that the invention comprises cathetersand scoring structures, where the scoring structures are positioned overthe balloons or other expandable shells of the catheter. The scoringstructures may be attached directly to the balloons or other shells, insome cases being embedded in the balloon material, but will more usuallybe formed as separate cage structures which are positioned over theballoon and attached to the catheter through attachment elements oneither side of the balloon. The expandable cages may be formed usingconventional medical device fabrication techniques, such as those usedfor fabricating stents, such as laser cutting of hypotube and othertubular structures, EDM forming of hypotubes and tubes, welding of wiresand other components and the like.

Typically, such expandable shell structures will comprise the attachmentelements and an intermediate scoring section between the attachmentelements. As illustrated in the embodiments above, the attachmentelements may be simple cylindrical or tube structures which circumscribethe catheter body on either side of the balloon or other expandableshell. The simple tube structures may float over the catheter body,i.e., be unattached, or may be fixed to the catheter body. A number ofalternative embodiments for the attachment elements will be described inconnection with the embodiments below.

The intermediate scoring sections may also have a variety ofconfigurations where at least some of the scoring elements willtypically be disposed in a non-axial configuration, i.e., in a directionwhich is not parallel to the axial direction of the expandable cage. Apreferred configuration for the intermediate scoring section comprisesone or more helical elements, generally as illustrated in the priorembodiments. Other exemplary configurations are set forth in theembodiments described below.

Referring now in particular to FIGS. 4 and 5, an expandable scoring cage100 comprises first and second attachment elements 102 and 104,respectively, and an intermediate scoring section 106 comprising aplurality of curved serpentine members 110. The serpentine members 110extend circumferentially in opposite directions in an alternatingmanner. This can be understood by observing a “rolled-out” view of theserpentine elements as illustrated in FIG. 5. A second alternativescoring cage structure 120 is illustrated in FIGS. 6-8. The scoring cage120 comprises first and second attachment elements 122 and 124 joined bya spine 126. A plurality of C-shaped scoring elements 128 and 130 areattached to the spine and extend in opposite circumferential directions.The shape of the element can be observed in FIG. 8. The oppositedirections may be observed in the rolled-out view of FIG. 7.

It will be appreciated that a variety of different circumferentialstructures may be used in place of the C-shaped structures of FIGS. 6-8.For example, a pair of opposed C-shaped partial ring structures may beutilized, as illustrated in FIG. 9. The C-shaped structures of FIG. 6 orthe double C-shaped structures of FIG. 9 can also be extended so thatthey wrap around a balloon more than one time, either over or under thespine structure 126.

The expandable cage structures 100 and 120 will each be mounted over adilatation balloon, such as the balloon of FIGS. 1-3, with theattachment elements secured to the catheter body on either side of thedilatation balloon. The tube or cylindrical attachment elements 102,104, 122, and 124 may simply float over the catheter body. In otherembodiments, however, it may be desirable to use an adhesive or othermeans for affixing either one or both of the attachment elements to thecatheter body. Having at least one floating attachment element, however,is often desirable since it can accommodate shortening of theintermediate scoring section as that section radially expands. In othercases, however, the individual scoring elements may possess sufficientelasticity to accommodate such shortening. For example, nitinol andother shape memory alloys possess significant stretchability, typicallyon the order of 8%, which in some instances will be sufficient toaccommodate any tension applied on the intermediate scoring section byradial expansion of the balloon.

Referring now to FIGS. 10-12, alternative attachment elements are shownon an embodiment of an expandable scoring cage 140 comprising threehelical scoring elements 142 which make up the intermediate scoringsection. A first attachment element 146 comprises a single serpentinering, as best illustrated in FIG. 11, while a second attachment element148 comprises a pair of tandem serpentine rings 150 and 152, as bestillustrated in FIG. 12. The use of such serpentine attachment structuresis beneficial since it permits crimping of either or both of thestructures onto the catheter body in order to fix either or both ends ofthe structure thereto. Usually, the single serpentine attachmentstructure 146 will be affixed to the catheter body while the doubleserpentine structure will be left free to allow movement of that end ofthe scoring cage to accommodate radial expansion of the underlyingballoon.

Referring now to FIGS. 13 and 14, a further alternative embodiment of anattachment element useful in the scoring cages of the present inventionis illustrated. Attachment element 180 includes a pair of serpentinerings 182 and 184, generally as shown in FIG. 13, in combination with acoil spring structure 186 located between said rings 182 and 184. Thecoil spring structure 186 includes three nested coil springs 190, eachjoining one of the bend structures 192 and 194 on the serpentine rings182 and 184, respectively. The structure of the spring structure andadjacent serpentine rings can be understood with reference to therolled-out configuration shown in FIG. 14.

The attachment structure 180 is advantageous since it permits a fixedattachment of the outermost ring 182 to the underlying catheter bodywhile the inner ring 184 remains floating and expansion and contractionof the intermediate scoring section, comprising helical elements 196, isaccommodated by the coil spring structure 186. Since the scoring cage isfixed to the catheter, any risk of loss or slippage from the balloon isreduced while sufficient compliance is provided to easily accommodateradial expansion of the intermediate scoring section. By attaching thestructures 180 to at least one, and preferably both ends of the scoringcage, the risk of interference with a stent is reduced.

In some embodiments, collars, such as those shown in FIGS. 1 and 2, orattachment elements, such as those shown in FIGS. 10-12, may comprise aflexible material that allows the collar or attachment element to expandwhile being mounted over the balloon catheter and then be collapsed tothe diameter of the catheter. The expandability of the collars and/orattachment elements may be achieved by a compliant memory material suchas nitinol or a polymer, or by use of a flexible serpentine design asshown in FIGS. 10-12. Where collars are used, the collar may be shapedor have a slit down the circumference (not shown) so that the collar maybe expanded during mounting over the balloon. Alternatively, the collarmay be oversized to accommodate the balloon diameter mounting, and thencrimped down to secure the secure the scoring structure to the catheterbody.

Yet another embodiment of the attachment element of the presentinvention includes an axial spring as shown in FIGS. 15 and 16. Theattachment element 200 includes a terminal serpentine ring 202 and anintermediate spring structure 204 including a number of axial serpentinespring elements 206. The nature of the serpentine ring elements 206 canbe observed in the rolled-out configuration of FIG. 16. Optionally, asecond serpentine ring 210 may be provided between the attachmentstructure 200 and the helical scoring elements of the intermediatescoring section 212.

The embodiments of FIGS. 13-16 comprise spring-like elements 186 and 204to accommodate axial shortening of the scoring structure upon radialexpansion. It will be appreciated that other metal and non-metal axiallyextensible structures could also be used in such attachment structures.For example, elastic polymeric tubes could be attached at one end to thescoring structures and at another end to the catheter body (or to aring, collar or other structure which in turn is fixed to the catheterbody).

Referring now to FIGS. 17 a and 17 b, a further embodiment of anangioplasty catheter 250 having an axially distensible attachmentstructure 258 is illustrated. External structure 252 is held overexpandable dilatation balloon 254 and is fixed at one end to the distalend 260 of catheter body 256. The external structure may comprise anystructure typically used for removal of plaque/thrombus from a vesselwall such as a scoring structure, cutting structure, or crushingstructure. The proximal end 262 of external structure 252 is connectedto the distal end 264 of attachment structure 258. The proximal end 266of attachment structure 258 is fixed to the catheter body 256. Asdescribed below, the attachment structure 258 may be configured toreduce forces applied on the external structure 252 and the catheterbody 256 during expansion and contraction of balloon 254.

In a preferred embodiment, attachment structure 258 comprises acylindrical over-tube, or compliance tube, made of an elastic material.Over-tube 258 generally has an inner diameter that is slightly greaterthan the outer diameter of the catheter body 256. Because only a smallsection of the proximal end of the attachment structure 258 is fixed tothe catheter body, the distal end 264 attached to external structure 252is free floating, and is free to slide axially and rotationally withrespect to catheter body 256. Attachment structure 252 may be fixed, forexample by adhesion, directly to the catheter body 256 and externalstructure 252, or to a collar or other intermediate attachment means.

As balloon 254 is expanded, external structure 252 expands incircumference and contracts axially along the catheter body 256,creating axial force A on attachment structure 258. Attachment structure258, fixed to the catheter at its end 266, axially stretches toaccommodate the axial movement of the external structure 252. Externalstructure 252 also tends to rotate about the catheter body 256, causinga torsional force T. The distal end 264 of attachment structure 258rotates through the full range of motion of scoring structure 252 toaccommodate torsional force T, while proximal end 266 remains stationarywith respect to catheter body 256.

The configuration illustrated in FIGS. 17 a and 17 b allows thecompliance of the expandable system to be controlled. Generally, whereone end of the scoring structure is free, the compliance of theexpandable system will be a combination of the compliance of the balloonand the scoring structure. However, because the ends of the expandablesystem shown in FIG. 17 are fixed at distal end 260 and proximal end266, the attachment structure controls the compliance of the expandablesystem.

The compliance of the system may be varied by any combination ofmaterial selection, wall thickness, or length of the over-tube 258.Over-tube 258 may comprise any elastomer, such as elastic polymer likeNylon, Pebax, or PET. Typically, compliance tube 258 is formed fromextruded tubing, but it may also comprise braided polymeric or metallicfibers, or wire mesh. A high memory metal such as nitinol or stainlesssteel may also be used. Where the compliance tube comprises an extrudedpolymeric tube, the wall thickness can vary in the ranges set forthabove, and the length of the tube can range from 1 cm to 10 cm. For thesame material, the thinner-walled and longer the tube, the morecompliant the system.

Referring to FIGS. 18 a-c, the compliance of angioplasty catheter 300may also be varied by creating one or more perforations in compliancetube 258. The perforations may comprise one or more slots in thecircumference of the tubing. The slots may comprise one continuous slotspiraling across the length of compliance tube 258, or may be a numberof slots aligned in any number of patterns, such as helical 312 orradial 314. The slots may also be any number of shapes, such as circularor rectangular, and may have a discreet length or be contiguous acrossthe surface of the compliance tube.

Referring to FIG. 19, the outside diameter of compliance tube 258 may betapered to facilitate delivery and retrieval of the scoring catheter 320from the treatment site within the lumen. Generally, the outer diameterwill be larger at the distal end 264 of the compliance tube 258 andsmaller at the proximal end 266 of the compliance tube. The outsidediameter D₁ at the distal end will vary depending on the profile of thescoring structure and balloon when collapsed but typically range from0.004 in. to 0.01 in. larger than the outside diameter D₂ at theproximal end. The outside diameter D₂ at the proximal end is generallyas close as possible to the outside diameter of the catheter body tocreate a smooth transition between the compliance tube and the catheter.As an example, for a catheter body having an outside diameter of 0.033in., outside diameter D₁ at the distal end may be 0.042 in. with aninner diameter of 0.038 in., the inner diameter providing clearancebetween the catheter body so that the distal end of the compliance tubecan move relative to the catheter body. Correspondingly, the outsidediameter D₂ at the proximal end may taper down to 0.0345 in., with aninner diameter of 0.034 in. to closely match the catheter body havingoutside diameter with enough clearance to be bonded to the catheter bodyby an adhesive.

The taper may run across the whole length of the compliance tube, oralternatively be only tapered at a section of the length of thecompliance tube. The tapered compliance tube 258 smoothes the transitionbetween the scoring structure and catheter body, and minimizes thelikelihood of the outer tube or scoring structure snagging or catchingon a portion of the luminal wall during delivery or retrieval of thecatheter.

Now referring to FIG. 20, an alternative embodiment of a scoringcatheter 350 is shown having a manipulator 360. The attachment structure258 is connected at its distal end 264 to the scoring structure 252.Instead of being secured directly to the catheter body 256, the proximalend 266 is attached to manipulator 360. Typically, the manipulator 360is positioned at the proximal end of the catheter body 256 and theattachment structure 258 extends from the scoring structure across thelength of the catheter body. Like the above embodiments, the attachmentstructure is capable of axially and rotationally extending toaccommodate foreshortening of the scoring structure as the shell isexpanded.

In some embodiments, the compliance of the scoring structure 252 andballoon 254 is controlled by actuating the manipulator during expansionor contraction of the radially expandable shell. In one aspect, theattachment structure 258 may be axially advanced with respect to thecatheter body 256 as the balloon is being inflated or deflated. Forexample, the attachment structure 258 may be pulled away from the distalend of the catheter body 256 while the balloon 254 is being expanded toconstrain the compliance of balloon. The attachment structure 258 mayalso be pulled away from the distal end of the catheter body 256 duringor after the balloon 254 is being deflated to minimize the profile ofthe balloon and scoring structure. Alternatively, the manipulator 360may be used to rotate the attachment structure 258 with respect to thecatheter body 256 to control the compliance of the balloon and scoringstructure during transition from a collapsed to expanded state and backto a collapsed state.

Now referring to FIGS. 21 and 22, a scoring cage structure 400 isillustrated having a two-layer laminated compliance tube 402. As shownin FIG. 22, the compliance tube 402 has a laminated structure 404 at atleast its distal end 410. The laminated structure holds the proximalends 408 of the scoring elements 406 as shown in broken line in FIG. 22.The scoring elements 406 may be sized to fit over the outside of thecompliance tube 402, as illustrated in FIG. 22, with the laminationcovering the elements. Alternatively, the compliance sleeve tube 402 maybe sized to fit inside of the scoring structure 406, with the laminatinglayer(s) formed over the elements 406 (not shown).

The laminating structure may be composed of a polymer similar to thecompliance tube 402, and may be heat shrunk or melted to thermally bondthe compliance sleeve to the compliance tube and sandwich the scoringstructure 406. Alternatively, an adhesive or other bonding method suchas ultrasonic or RF energy may be used to laminate the structure. Thelaminated structure, as shown in FIGS. 21 and 22, provides a smoothedtransition and strengthened bond between the scoring cage and theattachment structure. Such a smooth transition is a particular advantagewhen withdrawing the scoring cage from the vasculature.

FIGS. 23 and 24 illustrate scoring cage 400 positioned over anexpandable dilation balloon 412. As shown in FIG. 24, distal end 418 ofthe scoring structure may be coupled to the distal tip 414 of thecatheter body by an end cap 416. The end cap 416 may be composed of acompatible polymer and thermally bonded with the catheter body to fixdistal end 418 of the scoring structure to the catheter body.

Now referring to FIGS. 25-27, a method is illustrated for mounting anexpandable scoring cage 406 over a balloon catheter. The scoring cage406 is pre-expanded by loading it over an insertion tube 422 that has aninner diameter slightly larger than the outer diameter of the balloon412. A catheter body 420 having a balloon 412 is then inserted into theinner diameter of the insertion tube 422 and advanced until the balloon412 is appropriately positioned with respect to the scoring structure406, as illustrated in FIG. 26. The insertion tube 422 is then pulledback to allow the expanded scoring structure to collapse over theballoon 412 and the catheter body 420, as shown in FIG. 27. The scoringstructure 406 may then be secured at its distal end 418 to the distaltip 414 of the catheter body 420 and the proximal end 424 of the scoringstructure/attachment structure assembly to a medial location on thecatheter body 420.

As described thus far, the scoring structures and catheter apparatushave not included any drugs, active substances, or other coatings orfeatures related to releasing such drugs or substances into thevasculature or other body lumens. The scoring elements, however, can beeasily modified by a variety of known techniques for incorporating suchdrugs and active substances on, over, or within the structures of thescoring elements, as illustrated for example in FIGS. 28-34. The drugsand other active substances can be applied to one or more surfaceregions of the scoring elements by conventional techniques, such asdipping, painting, vapor deposition, spin coating, and the like. Theactive substances may be applied in an essentially pure form, i.e., inthe absence of any carriers, diluents, adjuvants, modifiers, enhancers,or the like. More commonly, however, the active substances will beapplied with or combined into a suitable carrier, matrix, or otherchemical structure which can facilitate or control release of the drugover a desired time period or immediately upon expansion of the scoringelement or shortly after being introduce to the body lumen. Inparticular examples, a resorbable or non-resorbable polymer matrix mayfirst be applied on at least a portion of an exposed surface of thescoring element, and the drug later absorbed into a porous structure ofthe polymer carrier matrix. Suitable materials for both resorbable andnon-resorbable polymers have been described above.

Referring to FIGS. 28 and 29, a scoring element or strut 500 can becoated with a pure or substantially pure layer 502 of a desired activesubstance. As shown in FIG. 28, the active substance layer 502 can beconfined to a limited surface or surfaces of the scoring element 500.Alternatively, as shown in FIG. 29, the active substance layer 502 cancover all or most of the exposed surfaces of the scoring element 500.

Referring now to FIGS. 30 and 31, scoring element 500 may be coveredwith a polymer matrix 504 which can cover a limited surface or surfacesof the element (as shown in FIG. 30), or all or most of the surfaces (asshown in FIG. 31). The active substance will be absorbed into porousregions of the polymer matrix 504 by conventional techniques. Resorbablepolymers, such as polylactic acids and polyglycolic acids, will degradeand be resorbed over time when exposed to a vascular environment. Insuch cases, release of the active substance from the matrix may beeffected by either the degradation where the drug is released as thepolymer decomposes or by combination of degradation and diffusionthrough the porous structure. In the case of non-resorbable polymers,the active substance will typically be released by a diffusion mechanismand the polymer will remain for sometime after diffusion hassubstantially stopped (although the polymer could degrade over a longertime period). In other examples, the polymer (e.g. poly ethylene oxide)can swell and the diffusion may be enhanced by the swelling process.

Referring now to FIG. 32, scoring element 510 may be modified to have awell 512, typically a plurality of wells, at least some of which willhold a polymer matrix 514. The polymer matrix may be degradable ornon-degradable, as described above, and will release an incorporatedactive substance by either of the mechanisms described.

As shown if FIG. 33, scoring element 520 may comprise one or more holes522, some or all of which contain a polymer matrix 524. The hole 522differs from the well 512 (FIG. 32) in that no bottom structure isprovided and the well is opened at each end. The active substance may beincorporated in the polymer matrix and released by any of the mechanismsdescribed above.

It will be appreciated that with either the well 512 or the hole 522,the polymer matrix may be composed of layers having different propertiesand/or include layers composed of different polymers or other materials.In this way, a variety of release mechanisms can be achieved.

Referring now to FIG. 34, a scoring element 530 having a sharpened orhoned ridge 532 can also be provided with an active substance. As shownin FIG. 34, the active substance is incorporated in a polymer matrix 534which is disposed a horizontal through hole 536. The through hole iscomposed of a resorbable or non-resorbable polymer and the activesubstance is incorporated therein and released by the mechanismsdescribed above. It will be appreciated, however, that the triangularelements, or any other scoring elements could also be coated with a drugdirectly or incorporated in a polymer matrix which is disposed overexterior surface(s) of the element. Additionally, it would be possibleto further coat the scoring element 530 of FIG. 34 with drug over all ora portion of its exterior surface(s) while also including the internallysequestered drug in the through hole 536.

Referring now to FIGS. 35, 36A, and 36B, use of the scoring elementstructures of the present invention for delivering an active substanceto a blood vessel will be described. Balloon 12 of dilatation device 10is expanded within a diseased region of a blood vessel 20, as generallydescribed above. Scoring elements 500 of the dilatation device haveincorporated drug, typically an anti-proliferative drug of the typedescribed above, incorporated in or over their surfaces and structures,by any of the means described above. As shown in FIG. 36A, in anexemplary embodiment, the scoring element 500 may penetrate intohardened plaque or thrombus PT as the balloon 12 is expanded. Thescoring element will penetrate into the plaque or thrombus PT andrelease drug, possibly a thrombolytic drug, into the plaque andthrombus. In other cases, a scoring element, such as the honed scoringelement 530 might be expanded by balloon 12 so that it enters into theblood vessel wall 20, as illustrated in FIG. 36B. In those cases, thedrug may be released directly into the intimal or other regions of theblood vessel wall.

It will be appreciated by persons skilled in the art that the presentinvention is not limited to what has been particularly shown anddescribed hereinabove. Alternate embodiments are contemplated that fallwithin the scope of the invention.

What is claimed is:
 1. A catheter comprising a catheter body having aproximal end and a distal end; a scoring element disposed near thedistal end of the catheter body; wherein the scoring element comprisesan active substance that is delivered to a luminal wall scored by thescoring element.
 2. A catheter as in claim 1, wherein the activesubstance is coated over at least a portion of an exposed surface of thescoring element.
 3. A catheter as in claim 2, wherein the activesubstance is incorporated in a polymeric carrier.
 4. A catheter as inclaim 3, wherein the polymeric carrier is resorbable in a vascularenvironment.
 5. A catheter as in claim 3, wherein the polymeric carrieris non-resorbable in a vascular environment.
 6. A catheter as in claim1, wherein the active substance is coated without a polymeric carrier.7. A catheter as in claim 1, wherein the active substance is carried inholes or wells formed in the scoring element.
 8. A catheter as in claim1, wherein the scoring element(s) is(are) generally linear and axiallyaligned over an expandable shell.
 9. A catheter as in claim 1, whereinthe scoring elements are formed as a resilient cage which is disposedover an expandable shell.
 10. A catheter as in claim 9, wherein the cagehas a resilient structure which expands with the shell and collapsesover the shell.
 11. A catheter as in claim 10, wherein the cagecomprises at least one helical scoring element.
 12. A method as in claim1, wherein the active substance comprises one or more of anantiproliferative agent, an antimitotic agent, an antiplatelet agent, analkylating agent, an antimetabolite, a platinum coordination complex, ahormone, an anticoagulant, a fibrinolytic agent, an antimigratory agent,an antisecretory agent, an anti-inflammatory agent, indole and aceticacids, an immunosuppressive agent, an angiogenic agent, an angiotensinreceptor blocker, a nitric oxide donor, an anti-sense olignucleotide, acell cycle inhibitor, a retinoid, a cyclin/CDK inhibitor, an HMGco-enzyme reductase inhibitor, and a protease inhibitor.
 13. A method asin claim 1, wherein the drug is incorporated within hydrogel and therelease of the drug is enhanced by the swelling of the hydrogel.
 14. Amethod with claim 1, wherein the active substance is hydrophobic drug.